Lung cancer is the single greatest cause of death from malignancy in both men and women in the US, exceeding that of the next three combined leading ncers (prostate, colon and breast cancer). Although smoking cessation is a key to lung cancer prevention, it remains a challenge. Finding effective preventive and treatment strategies for lung cancer are desperately needed. Cyclooygenase-2 (COX-2), a key mediator of inflammation, is an important target for lung cancer therapy and prevention because approximately 70% of lung adenocarcinomas have overexpression of COX-2 and regular use of aspirin and other NSAIDs is associated with a reduced risk of developing lung cancer in animal models and smokers. Regardless of the cardiac toxicity of selective COX-2 inhibitors, a growing body of evidence supports the etiological impact of COX-2 in lung cancer. Fish oil represents an attractive series of n-3 fatty acids (eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids) that modulate COX-2 activity while having beneficial cardiovascular effects. The strong link between COX-2 and fish oil-induced chemoprevention has been strengthen by recent findings of high consumption of long chain n-3 fatty acids lowering their risk of prostate cancer and this protective effect being more pronounced in men carrying a particular COX-2 variant. The ultimate goal of this proposal is to define the optimal dose of EPA and relevant fish oil products to maximize the chemopreventive effects of fish oil against human lung cancer and to identify an appropriate molecular target of fish oil for prevention of lung cancer. We will determine the chemopreventive role of EPA and fish oils using a urethane- induced mouse lung cancer model with and without expression of COX-2, as well as the K-ras mutation mouse lung model. We will also evaluate the molecular mechanisms associated with EPA-induced tumor growth suppression by studying the biological effects of PGE2 and the EPA metabolite PGE3 in premalignant and lung cancer cells and their interaction with PGE2 receptors. The critical role of EPA-derived PGE3 in lung cancer prevention using the urethane-induced mouse lung cancer model with or without expression of EP receptor, particularly EP2 and EP4 receptors, will be further studied. This proposal intends to define a novel targeted natural chemopreventive agent against lung cancer.